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Endothelin receptor type B (ETB)‐deficient pregnant rats have exaggerated placental ischemia‐induced hypertension
Author(s) -
Dent Edward Alexander,
Spradley Frank Travis,
Granger Joey P
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.851.8
Subject(s) - medicine , endocrinology , preeclampsia , endothelin receptor , blood pressure , ischemia , endothelin 1 , fetus , receptor , pregnancy , biology , genetics
Preeclampsia (PE) is a pregnancy‐specific disorder of new‐onset hypertension that threatens the lives of both mother and fetus. While the pathogenesis of PE is unclear, studies have implicated placental ischemia. Indeed, reduced uterine perfusion pressure (RUPP)‐induced placental ischemia in experimental animals stimulates the release of soluble factors into the maternal circulation, causing vascular dysfunction and hypertension. Pharmacological blockade of the vasoconstrictive endothelin type A receptor (ETA) abolishes RUPP‐induced hypertension. Although blockade of vasodilatory ETB receptors increases blood pressure during late pregnancy in rodents and placental ischemia has been shown to reduce ETB receptor expression, the importance of the ET/ETB receptor pathway in blood pressure regulation during pregnancy or in response to placental ischemia is unclear. Therefore, we tested the hypothesis that ETB deficiency results in exaggerated placental ischemia‐induced hypertension. At eighteen weeks old, ETB deficient (def) and transgenic control (Tg) timed‐pregnant rats were generated using Wistar Hannover males. Rats underwent RUPP or Sham surgeries at gestational day 14, with assessment of mean arterial blood pressure (MAP, carotid catheter) and pregnancy weights and plasma collection at day 19. This resulted in 4 groups: Sham Tg (N=13); RUPP TG (N=10); Sham ETB def (N=11); and RUPP ETB def (N=6). MAP was greater in Sham ETB def compared to Sham Tg (109±3 vs. 79±3 mmHg, P<0.05). MAP levels were increased by RUPP in both Tg (99±3 mmHg, P<0.05) and ETB def (139±6 mmHg, P<0.05), but the degree of this RUPP hypertension was exaggerated in ETB def rats (30 vs. 20 mmHg). Average fetal weights were lower in Sham ETB def than Sham Tg (1.79±0.11 vs. 2.24±0.06 g, P<0.05) and were reduced by RUPP in Tg (2.08±0.06 g, P<0.05) but not further reduced in RUPP ETB def (1.66±0.13 g). Average placental weights were similar in Sham ETB def and Sham Tg (0.52±0.01 vs. 0.50±0.01 g). RUPP reduced placental weights in Tg (0.43±0.03 g, P<0.05) but not RUPP ETB def (0.55±0.04 g). Placental sufficiency (fetal weight divided by placental weight, a marker of placental nurturing capacity) was lower in Sham ETB def compared to Sham Tg (4.05±0.15 vs. 4.58±0.20, P<0.05). This was not reduced by RUPP in Tg (4.41±0.36) but was further reduced in RUPP ETB def (3.11±0.38, P<0.05). Circulating levels of cGMP, a surrogate measure of bioavailability of the vasodilatory nitric oxide (NO), were reduced in Sham ETB def compared to Sham Tg (43±5 vs. 178±18 pg/mL, P<0.05), which were reduced by RUPP in Tg (18±3 pg/mL), but not further reduced in RUPP ETB def (35±11 pg/mL). In conclusion, these data not only suggest an important role for ETB in blood pressure regulation during normal pregnancy but also in buffering the response to placental ischemia‐induced hypertension. Support or Funding Information K99HL130577, HL51971, P20GM104357